CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: March 01, 2022
Expiration: February 28, 2023
To obtain the best outcomes with CML treatment, it is critical that patients be monitored according to current recommendations.17
First, at the time of diagnosis, a bone marrow aspiration should receive a full karyotype test to identify whether the patient may have additional chromosomal abnormalities. A PCR analysis should then be conducted to ensure it can detect BCR-ABL1 transcripts; the occasional patient may have atypical BCR-ABL1 transcripts that are not identified by PCR, meaning the patient cannot be followed with PCR.
After they start therapy, patients should be assessed every 3 months by both fluorescence in situ hybridization (FISH) and PCR, with a repeat bone marrow aspiration at 6-12 months after the start of therapy to identify any additional chromosomal abnormalities.
Once the patient reaches a complete cytogenetic response or the equivalent (eg, ≤1% transcript levels), he or she can be monitored with PCR at 6-month intervals. Of note, the European LeukemiaNet guideline recommends every 3 months, but every 6 months is considered adequate. That said, for a patient with any changes in doses or other concerns, monitoring every 3 months is appropriate.
If transcript levels increase, patients need to be monitored more frequently. For example, although every 3 months tends to be sufficient, for a patient with a >1-log increase in the BCR-ABL1 transcript levels, repeat monitoring should be done within a month to confirm whether it is a true loss of response (vs test variability). Physicians need to remember to not act based on a single measurement, as a technical issue with the assay could have caused the elevation in BCR-ABL1 transcript levels rather than a loss of response.
BCR-ABL1 mutation analyses are only needed when there is clear evidence of resistance to therapy, or a need to change the TKI. They are not done at diagnosis, because it is very unlikely that the assay will identify any mutations at that time. Also, if a patient doesn’t reach a molecular response, a mutation analysis is unlikely to find a mutation.
Typically, a change in therapy is recommended only if patients lose their CCyR or if the transcript levels go up more than 1%. Not achieving an MMR is typically not enough reason to change therapy.
Cytogenetic and molecular responses are key to guiding therapy choices in CML. A CCyR is defined as having no Philadelphia chromosome in 20 metaphases (or a BCR-ABL1IS <1%).18 This can be assessed by chromosome banding analysis or FISH. Achieving a CCyR is the gold standard for response because it is associated with improved survival; in one study, 5-year OS rates were 97% with CCyR vs 74% with no CCyR.19 This is also why therapy typically isn’t changed unless a patient loses a CCyR.
An MMR is associated with improved survival, but that is because it also includes CCyR. MMR in the context of only patients who have a CCyR does not improve OS, but it is associated with an improvement in progression-free survival (PFS).20,21 Deeper molecular responses, for example, MR4 and particularly MR4.5, are important considerations for treatment-free remission and will be discussed next.
Early molecular response (EMR) is defined as ≤10% BCR-ABL1 transcripts at 3 months and is associated with improved PFS and OS with frontline therapy; 5-year PFS and OS rates with EMR compared with no EMR are as high as 99% vs 72% and 99% vs 79%, respectively.
To date, it remains unclear what to do if a patient doesn’t achieve this response at 3 months; no study has shown long-term benefit of a change in therapy in this setting. Initial findings from the phase IIb DASCERN study, which assessed the outcomes of early switch to dasatinib in patients with suboptimal response to imatinib, have suggested that an early change in therapy can improve MMR at 12 months, but no PFS or OS benefit is evident in the short follow-up.22
Multiple studies of second-generation TKIs in CML have shown significant benefit for achieving a CCyR at 3 months, as shown in these event-free survival and OS curves.23 Patients who reach these responses early on have a better probability of survival.
It is important to understand some of the variabilities inherent to molecular monitoring. The gold standard is quantitative real-time PCR.24 Of importance, these tests only can quantify patient samples that have typical BCR-ABL1 transcripts, for example, B2A2, B3A2, E13A2, and E14A2, which includes the majority of patients, but some have a different transcript that is not measurable by the standard assays. These results allow quantification of the oncogenic fusion gene BCR-ABL1 mRNA relative to the expected control genes. In the United States, most of the tests use ABL as the control, but other control genes can be used. Importantly, if ABL is the control gene and is expressed at very high levels, for example, at the time of diagnosis or early in the course of therapy, the level itself is not predictive. It is used as a control only to detect these transcripts at the time of diagnosis and rule out the possibility that the patient may have an atypical transcript.
Other techniques like nested PCR have greater sensitivity.23 Nested PCR is less commonly used because the sensitivity of real-time PCR has increased significantly beyond the older standard of qualitative PCR.
Multiplex PCR can cover many other types of rearrangements, for example, the P190 rearrangement seen in acute lymphocytic leukemia, or an atypical transcript by identifying the BCR-ABL1 breakpoint. Multiplex PCR is not quantitative to the same extent, and not standardized, like the other tests.
Digital PCR is an investigational tool, but it is much more sensitive and is increasingly being used for patients who stop therapy.
There are many factors that affect the PCR test,25 including a coefficient variability that can be half a log or even 1 log. There are even variabilities within the standardization, such as degradation of mRNA during transportation. Also, continued standardization is not consistently done in all patients. HCPs need to be aware of current best practices, such as not testing more frequently than every 3 months.
It is critically important for physicians to be able to distinguish between a response that is a treatment failure and a response that is a warning but without failure.12 Guideline recommendations are available from the European LeukemiaNet and the National Comprehensive Cancer Network.
This table provides guidance on when to consider taking action to change therapy over time. Failure is defined as when a change in therapy is clearly indicated, for example, if a patient has no hematologic response at 3 months and then has transcripts >10% at 6 months. Patients who are failing may be able to switch TKIs and may be candidates for allogeneic stem cell transplant, and a bone marrow examination might be warranted to reassess CML phase and clonal evolution, plus the BCR-ABL1 mutational profile.
By contrast, the warning category represents patients who need to be more closely monitored but who do not necessarily need a change in therapy. However, these patients should be prepared to change therapy, and physicians should assess their treatment adherence and the potential for drug–drug interactions.
Options After First-line TKI Failure
If a patient has clearly identified treatment failure with TKI resistance, it is important to do a full assessment.12 That includes a bone marrow examination to look at the full karyotype and a mutation analysis to help direct what subsequent TKI to use. Different TKIs target different mutations, but only 30% to 50% of patients will have a mutation and only a handful of mutations are informative for selecting a TKI. Still, it is important to do a mutation analysis.
Before confirming that a patient with CML has developed TKI resistance, ascertain whether he or she has been adherent to the treatment, and look for potential drug–drug interactions.
Arterial occlusive events are a concern in patients with CML treated with ponatinib, with a cumulative incidence correlated with higher doses and longer treatment duration.30 Because of this risk, trials like OPTIC have implemented response-directed dose adjustment to determine whether lower starting doses would preserve efficacy and decrease the risk of toxicity.31
In this study, ponatinib was evaluated at different starting doses in 94 patients with chronic-phase CML and either resistance to at least 2 TKIs or with the T315I mutation. Results showed clearly that 45 mg as the starting dose is the most effective, with an overall response rate of 44% compared with only 29% with 30 mg. Starting with 45 mg has decreased the incidence of arterial occlusive events to only 9.6%, compared with, historically, approximately 25% to 35% of patients. Five patients had grade ≥3 treatment-emergent arterial occlusive events, and 4 patients had to discontinue treatment.
This table shows key data from studies of 3 second-generation TKIs—dasatinib, nilotinib, and bosutinib—after imatinib failure.3,26-28 Importantly, the CCyR rate is only 40% to 50%. Major cytogenetic responses were seen in 56% to 63%. Two-year PFS rates ranged from 64% to 85%.
As mentioned previously, patients should be monitored for mutations in order to guide the choice of second-line TKI. If a patient has already received a second-generation TKI as frontline therapy, another second-generation TKI is not the best second-line approach, and a third-generation TKI or novel STAMP inhibitor should be considered.
Long-term OS is typically good with targeted therapies for Ph+ CML. In the CA180-034 phase III trial of dasatinib in patients with progression on imatinib, the OS rate at 7 years of follow-up was 63% in imatinib-resistant patients and 70% in imatinib-intolerant patients.26 This study randomized patients to different doses and schedules, and the results established 100 mg once daily as the optimal approach, particularly with regard to safety. However, although the OS is very good, the PFS rate was only 42% overall, and many patients eventually lose their response to dasatinib and some may progress.
Studies in T315I+ CML and/or CML With ≥2 Previous Therapies
This table shows long-term outcomes from a phase I/II study of bosutinib as third-line therapy in patients with chronic-phase CML after prior TKI failure.29 In this study, response rates declined with subsequent lines of therapy. Sustained MCyR rates at 4 years were 43% in patients resistant to both imatinib and dasatinib, compared with 87% if only intolerant to both agents vs 78% for those with resistance to imatinib and nilotinib. Fortunately, the third-generation BCR-ABL1 kinase inhibitors provide much better responses.
Ponatinib was the first of the third-generation BCR-ABL1 kinase inhibitors. PACE was a phase II trial of ponatinib in Ph+ leukemias resistant or intolerant to dasatinib or nilotinib.
Five-year results in the cohort of patients with chronic-phase CML (n = 267) and resistance to at least 1 previous TKI showed a MCyR rate of approximately 60%, most of which are actually CCyRs.10 As shown here, these are deep molecular responses, with nearly 25% of patients achieving MR4.5. In addition, these responses are very durable: At 5 years, 82% of patients maintained their MCyR and 59% maintained their MMR.
Improved management of ponatinib can optimize the risk–benefit ratio. As shown here, efficacy is significantly improved by starting with 45 mg: 51.6% of patients achieved fewer than 1% BCR-ABL1 transcripts by 1 year vs 35.5% with 30 mg.31 Of note, the risk of arterial occlusive events decreased with lower doses.
Asciminib, a first-in-class STAMP inhibitor, has a different mechanism of action than other anti–BCR-ABL1–targeting therapies. Asciminib inhibits the myristoyl pocket rather than the ATP-binding pocket. Following a phase I/II trial showing clinical benefit in patients with CML who had failed multiple TKIs or who had the T315I mutation, the phase III ASCEMBL trial was conducted to compare asciminib to bosutinib.32
In ASCEMBL, 233 patients with chronic-phase CML and at least 2 prior TKIs were randomized to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. The primary endpoint was the MMR rate at 24 weeks. Secondary endpoints included an MMR rate at Week 96 (meeting no treatment failure criteria before Week 96), safety and tolerability, CCyR/MMR rates, time to and duration of CCyR/MMR, time to treatment failure, PFS, OS, and pharmacology parameters.
At 48 weeks, the MMR rate with asciminib was more than double than with bosutinib, at 29% vs 13%, respectively. Likewise, the percentage of patients with BCR-ABL1 ≤1% was 42% vs 19%. Durability was good, with more than 95% of patients retaining their MMR for at least 48 weeks, and at least 50% retaining BCR-ABL1 ≤1%. Lastly, the cumulative incidence of BCR-ABL1 ≤1% also showed superiority of asciminib, at 51% vs 34% with bosutinib.
As shown here, for patients who have failed imatinib and a second-generation TKI, the optimal third-line choice is a third-generation TKI. In this analysis, with the caveat of a limited number of patients, ponatinib was more strongly associated with CCyR than either bosutinib, dasatinib, or nilotinib in patients with CML who failed imatinib and a second-generation TKI.33
Increasingly, discontinuing treatment is a goal of therapy for CML patients who are doing well. Specific criteria must be met to qualify for treatment discontinuation, and the patient must meet all of them.34,35 The criteria are that the patient (a) must have typical BCR-ABL1 transcripts at diagnosis (to allow assessment on the International Scale), (b) has had at least 5 years of TKI therapy, (c) had a deep molecular response such as MR4.5 for 2-5 years or more, (d) agrees to frequent high-quality monitoring, and (e) has made the well-informed decision to stop therapy.
After treatment is stopped, the patient should be monitored monthly during the first 6 months, then every 6 weeks during the next 6 months, then every 3 months going forward. However, only approximately 50% of patients will be able to maintain their response. So, if a patient loses an MMR, he or she has to resume therapy. With the treatments available today, only about 25% of all patients with CML can realistically expect to be able to discontinue therapy for a sustained period—possibly indefinitely.
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